Our prior work focused on understanding mechanisms that contribute to the development of a stable, mature myotendinous junction (MTJ). Results obtained during the past funding cycle identified essential roles for evolutionarily conserved proteins not just in the formation, but also in the maintenance, of muscle-tendon interactions. Interestingly, continued maintenance of MTJ formation is intimately linked to muscle homeostasis. The overall goal during the next funding period is to understand how proteostasis is regulated in the context of cell homeostasis. The inability to remove protein aggregates in non-dividing cells such as neurons or muscles is a key factor in the development and progression of neurodegenerative diseases and myopathies and is a cellular hallmark of aging cells. While protein aggregate diseases share common features, it is widely assumed that the molecular pathways that lead to protein aggregation cannot be explained by a single mechanism. In protein aggregation disease that cause myopathies, a general trend has emerged in which aggregated proteins and organelles accumulate in regions devoid of muscle tissue. However, the cellular and mechanical triggers that initiate Z-disk disintegration and myofiber displacement are unclear. Here we employ mutations in conserved Drosophila genes as an entry point to uncover cellular and molecular mechanisms that lead to protein aggregation and ultimately cellular degeneration using muscle as a model cell type. Overall, we expect to uncover unrecognized aspects of, including, but not limited to: uncovering novel components that contribute to proteostasis; identifying muscle targets of kinase activity; and determining how autophagy cooperates in the clearance of protein aggregates. A powerful combination of genetic analysis, biochemistry, cell biology, and live imaging approaches will address these questions. We expect that this project will fundamentally advance our understanding of how protein degradation is regulated to prevent cellular degeneration and to provide fresh insights into how protein aggregates can be effectively cleared to reduce disease states.
Non-dividing muscle and nerve cells have limited options to clear harmful biological insults. One such insult is the progressive accumulation of protein aggregates that destroys cellular function and may result in death. The overall goal of this application is to understand how cells normally clear aggregated proteins to eventually develop successful therapeutic strategies to maintain healthy cells.
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